REGULATION OF THE TYPE II TGF -B- RECEPTOR

II 型 TGF -B- 受体的调节

• 批准号: 2724734
• 负责人: A. ANGIE RIZZINO
• 金额: $ 19.76万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-14 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2724734
• 关键词: biological signal transduction; cell differentiation; cell line; chromatin; gene expression; genetic mapping; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; growth factor receptors; regulatory gene; tissue /cell culture; transcription factor; transforming growth factors

DESCRIPTION: (adapted from the investigator's abstract) It is widely believed that the loss of transforming growth factor-beta- receptors (TGF-beta- R) contributes significantly to carcinogenesis. Functional TGF-beta-R comprise several gene products, including two essential signaling components, the type I TGF-beta-R and the type II TGF-beta-R (TbetaR-II). In several instances in which tumor cells fail to express the TbetaR-II gene at the RNA or protein level, no apparent structural mutations within the coding region of the gene have been observed. This suggests that defects in the promoter region of the TbetaR-II gene and/or in the mechanisms regulating the transcription of the TbetaR-II gene play key roles in its aberrant expression in certain neoplasms. Thus, Dr. Rizzino feels that it is important to understand how the TbetaR-II gene is regulated. Before attempting to understand why this gene is expressed aberrantly in tumor cells, it is important to understand how this gene is regulated normally. Embryonal carcinoma (EC) cells are well suited to achieving this objective, since the differentiation of these cells leads to the turn on of TGF-beta-R. Efforts to understand how the TbetaR-II gene is regulated have shown that differentiation of EC cells leads to the transcriptional activation of this gene. Based on work with the promoter region of the human TbetaR-II gene, two hypotheses have emerged. First, the transcription of the TbetaR-II gene is influenced significantly by at least two positive and two negative regulatory regions. Second, the transcription factor complex NF-Y, which binds to one of the negative regulatory elements in the gene, reduces the transcription of the TbetaR-II gene by interfering with the binding or function of transcription factors that bind to neighboring positive regulatory elements. To test these hypotheses, four Specific Aims are proposed: 1) determine which transcription factors interact with one another to regulate the transcription of the TbetaR-II gene, 2) isolate the promoter region of the murine TbetaR-II gene and map precisely the location of the regulatory elements, 3) identify the transcription factors that bind to the regulatory elements of the TbetaR-II gene, and 4) determine whether differentiation of EC cells alters the chromatin structure of the TbetaR-II gene and the binding of transcription factors to critical regulatory elements. Together, Dr. Rizzino feels that these studies will not only help determine how the TbetaR-II gene is regulated normally, but they will also provide the groundwork for understanding why this gene is aberrantly expressed in tumors.

描述：（改编自研究者摘要） 人们普遍认为，转化生长因子β- 受体（TGF-β- R）的表达对致癌作用有显著贡献。 功能性TGF-β-R包含几种基因产物，包括两种 必需的信号成分，I型TGF-β-R和II型TGF-β-R， TGF-β-R（TbetaR-II）。在几个肿瘤细胞不能 为了在RNA或蛋白质水平上表达TbetaR-II基因， 基因编码区的结构突变已经被 观察这表明，在启动子区的缺陷， TbetaR-II基因和/或调节转录的机制 TbetaR-II基因在某些细胞中异常表达中起关键作用 肿瘤。 因此，Rizzino博士认为，重要的是要了解 TbetaR-II基因受到调控。在试图理解为什么 基因在肿瘤细胞中表达异常， 了解这个基因是如何正常调节的。胚胎癌 细胞非常适合实现这一目标，因为 这些细胞的分化导致TGF-β-R的开启。 对TbetaR-II基因调控机制的研究表明， EC细胞的分化导致转录激活， 这个基因。基于对人类启动子区的研究， TbetaR-II基因，出现了两种假说。第一，转录 TbetaR-II基因的表达受至少两种 正调控区和负调控区。第二，转录 因子复合物NF-Y，其结合到负调节因子之一， 基因中的元件，减少TbetaR-II基因的转录 通过干扰转录因子的结合或功能 与邻近的正调控元件结合。测试这些 假设，提出了四个具体目标：1）确定哪些 转录因子之间相互作用， 2）分离TbetaR-II基因的启动子区， 小鼠TbetaR-II基因，并精确地绘制了TbetaR-II基因的位置。 调控元件，3）鉴定结合至 TbetaR-II基因的调节元件，以及4）确定是否 EC细胞的分化改变了细胞的染色质结构， TbetaR-II基因与转录因子结合的关键机制 监管要素。总之，Rizzino博士认为这些研究将 不仅有助于确定TbetaR-II基因是如何正常调节的， 但它们也将为理解为什么会这样提供基础 基因在肿瘤中异常表达。